clinical Consultation Dexmedetomidine

clinical c o n s u ltat i o n

Dexmedetomidine for opioid and benzodiazepine

withdrawal in pediatric patients
Alexandra Oschman, Tara McCabe, and Robert J. Kuhn

O
pioids and benzodiazepines
are mainstays of sedation and
analgesia in the pediatric inten-
sive care unit (PICU). Use of these
medications often requires a balance
of pain relief and sedation, along
with the management of narcotic
withdrawal. Narcotic withdrawal
syndromes were first described in the
neonatal population in the 1970s.1,2
Only in the last 20 years have narcotic
withdrawal syndromes been recog-
nized in other pediatric patients;
most cases are a result of iatrogenic
exposure to narcotics during long
hospital stays.2,3 Dexmedetomidine
is an a2-adrenergic receptor agonist
that has the potential to decrease nar-
cotic withdrawal symptoms.4 While
published data are available regard-
ing the use of dexmedetomidine as
an adjunct for sedation and analgesia
in pediatric patients, there are limited
data on the use of dexmedetomidine
for pediatric narcotic withdrawal
syndromes. For this review, clinical
studies were evaluated to assess the
appropriateness of dexmedetomi-
dine use in this population.
Withdrawal may be difficult to as-
sess in the PICU due to the wide vari-
ability and nonspecificity of objective
Purpose. The published literature on the
use of dexmedetomidine as an adjunct
to sedation and analgesia in the manage-
ment of pediatric narcotic withdrawal was
reviewed.
Summary. Pediatric narcotic withdrawal
syndromes are reported to be increasingly
frequent in pediatric intensive care units.
A number of tools specifically designed
for assessment of withdrawal in newborns
and infants are in current use, including
the widely used Finnegan Scoring System.
A limited number of studies and case re-
ports suggest that dexmedetomidine, an
a2-receptor agonist with a mechanism of
action similar to that of clonidine but with
greater a2-receptor specificity, might have
a role in the treatment of pediatric with-
drawal (by blunting withdrawal symptoms
without causing respiratory depression
and by permitting shorter narcotic taper-
ing schedules) and also in the prevention of
pediatric narcotic withdrawal (by reducing
narcotic requirements). Potential adverse
effects associated with dexmedetomidine
use in pediatric patients are generally asso-
and subjective withdrawal symp-
toms. Several retrospective studies
have reported withdrawal symptoms
in 35–57% of children receiving con-
tinuous infusion opioids and benzo-
diazepines.3 The increased awareness
ciated with use of bolus doses and mainly
involve central nervous system effects (e.g.,
hypotension, bradycardia), with no hemo-
dynamic manifestations. When bolus doses
are used, strategies described in published
reports entail a loading dose of 0.5–1.0
mg/kg administered over 5–10 minutes, fol-
lowed by a continuous infusion at 0.1–1.4
mg/kg/hr for a period of 1–16 days. More re-
search is needed to define the optimal use
of dexmedetomidine in the management
of pediatric narcotic withdrawal.
Conclusion. A limited body of published
evidence from retrospective studies and
case reports suggests a potential role for
dexmedetomidine as an adjunct therapy to
provide sedation and analgesia to reduce
narcotic withdrawal symptoms in pediatric
patients.
Index terms: Benzodiazepines; Dexme-
detomidine hydrochloride; Dosage; Drug
withdrawal; Hospitals; Mechanism of ac-
tion; Opiates; Pediatrics; Sympathomimetic
agents; Toxicity
Am J Health-Syst Pharm. 2011; 68:1233-8
of narcotic withdrawal in the pedi-
atric population has led to questions
as to how to best prevent and treat
pediatric narcotic withdrawal.
Withdrawal symptoms are often
related to sympathetic system acti-

Alexandra Oschman, Pharm.D., is Neonatal Intensive Care Unit
Clinical Pharmacist Specialist, Children’s Mercy Hospital and Clin-
ics, Kansas City, MO. Tara McCabe, Pharm.D., is Pediatric Clinical
Pharmacy Specialist, Shands at the University of Florida Hospital,
Gainesville. Robert J. Kuhn, Pharm.D., is Associate Director of
Pharmacy Services, Kentucky Children’s Hospital, University of
Kentucky Healthcare.
Address correspondence to Dr. Oschman at Children’s Mercy
Hospital and Clinics, 2401 Gillham Road, Kansas City, MO 64108
(aoschman@cmh.edu).
The authors have declared no potential conflicts of interest.
Copyright © 2011, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/11/0701-1233$06.00.
DOI 10.2146/ajhp100257

Am J Health-Syst Pharm—Vol 68 Jul 1, 2011 1233

 clinical consultation
The Clinical Consultation section features
articles that provide brief advice on how to
handle specific drug therapy problems. All
articles are based on a systematic review
of the literature. The assistance of ASHP’s
Section of Clinical Specialists and Scientists
in soliciting Clinical Consultation submis-
sions is acknowledged. Unsolicited submis-
sions are also welcome.
vation, which includes tachycardia,
tachypnea, diaphoresis, and hyper-
pyrexia. Other common symptoms
are vomiting and diarrhea. In severe
cases, muscle convulsion and seizure
activity can occur.3,5-8 There are sev-
eral case reports of movement dis-
orders in children upon removal of
fentanyl or fentanyl and midazolam
for sedation; the movement disorders
included tremor, clonus, and choreic
facial movements.3,5,6
Manifestations of withdrawal are
related to the half-life of the narcotic
used; thus, the onset can vary from
hours to days. Medications with
active metabolites (e.g., morphine,
diazepam) are more likely to be as-
sociated with delayed withdrawal
onset. Patients with renal or hepatic
dysfunction may also experience
delayed withdrawal onset due to
their decreased ability to metabolize
and clear drugs.7 Drug elimination is
impaired to some degree in critically
ill patients as a result of probable hy-
poperfusion of the liver and kidneys
during the acute-illness phase. This
phenomenon can result in accumu-
lation of drug with prolonged use
and may influence the development
of withdrawal syndromes.
Opioid and benzodiazepine
withdrawal
Benzodiazepines provide sedation
via attachment to g-aminobutyric
receptors in the central nervous sys-
tem (CNS). The result is a decrease
in sympathetic outflow, which results
in sedation. Withdrawal has been
seen with a wide duration of use:
from 11 hours to two months. A
1234 Am J Health-Syst Pharm—Vol 68 Jul 1, 2011
Dexmedetomidine
retrospective chart review involving
40 pediatric patients found a 35%
rate of withdrawal in patients receiv-
ing mi­d azolam continuous infu-
sions.9 Other research indicates that
patients who receive a cumulative
midazolam dosage of 60 mg/kg or
higher are more likely to experience
withdrawal.7,8
Fentanyl is a rapid-acting, syn-
thetic mu–opioid receptor agonist.10
Fentanyl is a highly lipid-soluble
drug and distributes effectively into
adipose tissue. Acidosis can increase
the capacity of fentanyl to bind to
muscle and adipose tissue, resulting
in prolongation of fentanyl storage.11
The delayed release of fentanyl from
adipose tissue may result in delayed
withdrawal.
The rate of withdrawal in pediat-
ric patients receiving fentanyl con-
tinuous infusions has been reported
as 57%.10,12 Katz et al.10 performed a
retrospective study of 23 infants who
received at least 24 hours of contin-
uous infusion fentanyl. Withdrawal
was seen in 13 of the 23 infants;
those who experienced withdrawal
had higher mean cumulative fentan-
yl dosages (2.96 mg/kg versus 0.53
mg/kg) and a longer mean duration
of fentanyl use (13.1 days versus
3.8 days). Other studies have shown
that a total fentanyl dosage of ≥1.5
mg/kg or a duration of use of 5 days
or more resulted in a 50% rate of
withdrawal. Patients receiving dos-
ages of ≥2.5 mg/kg or infusions last-
ing 9 days or more had a 100% rate of
withdrawal.2,7,8
The choice of pharmacotherapy
for prevention of narcotic withdraw-
al through use of tapering schedules
varies among institutions. The most
common agents used are morphine,
methadone, diazepam, lorazepam,
and phenobarbital. Regardless of the
medication chosen, an important
aspect is observation for signs, symp-
toms, and alleviation of withdrawal.
Withdrawal assessment scales
Assessment of pediatric narcotic
withdrawal is not standardized, and
a variety of approaches are in cur-
rent use.3,7,8 Using a scoring system
is an effective way to standardize the
evaluation of narcotic withdrawal,
and there are several scoring systems
available; while all have limitations,
they can help guide assessment for
narcotic withdrawal. Of the six scales
currently used for assessment of
pediatric withdrawal, several were
developed specifically for use in new-
borns and infants.
One widely used assessment tool
is the Neonatal Abstinence Score
developed by Finnegan et al.1 for
evaluation of newborns and infants
for withdrawal resulting from mater-
nal exposure to narcotics. Using this
method, also known as the Finnegan
Scoring System (FSS), patients are
assessed for the presence and severity
of 31 signs and symptoms in three
categories (CNS, gastrointestinal, and
metabolic/vasomotor/respiratory);
each sign or symptom is assigned a
score of 1–5, with an aggregate score
of 0–7 indicating mild withdrawal,
a score of 8–11 indicating moderate
withdrawal, and a score of 12–15
indicating severe withdrawal. As
several of the signs and symptoms
are specific to neonates and infants,
the use and clinical utility of the
Finnegan method in older pediatric
patients are limited; the method also
is thought by some to be too com-
plicated for use in the PICU setting.3
Nonetheless, the method can be use-
ful in the clinical assessment of opi-
oid and benzodiazepine withdrawal
in children.
Other clinical assessment tools
specifically designed for assessment of
withdrawal in children receiving long-
term opioid therapy in the PICU in-
clude the Sedation Withdrawal Score
(SWS), derived from assessment of 12
neonatal signs and symptoms,13 and
the Opioid–Benzodiazepine With-
drawal Scale (OBWS), which is used
to evaluate 16 parameters adapted
from the Finnegan method.14 The
validity and reliability of the SWS

and OBWS have not been firmly
established.
Use of dexmedetomidine
Current pharmacotherapy regi-
mens for narcotic withdrawal consist
of other narcotic agents. Clonidine
has been shown to have a role
in neonatal abstinence syndrome
(NAS) and is used as an adjunctive
therapy for opioid withdrawal in
adults.15 Agathe et al.15 found that the
use of oral clonidine hydrochloride
1 mg/kg/dose every four hours as an
adjunct to diluted tincture of opium
resulted in a 27% decrease in the me-
dian length of therapy for NAS.
Dexmedetomidine’s chemical
structure is similar to that of cloni-
dine, but the former has a greater
specificity for the a2- (as opposed
to a1) receptor (1620:1 for dexme-
detomidine versus 220:1 for cloni-
dine).4 With both drugs, activation
of a2-receptors results in analgesia,
sedation, and anxiolysis. Due to the
drugs’ similar mechanisms of action,
it has been hypothesized that dexme-
detomidine, like clonidine, may have
a role in the management of opioid
withdrawal syndromes.
When used as an adjunct for seda-
tion and analgesia, dexmedetomi-
dine was administered at a continu-
ous infusion range of 0.1–1.4 mg/kg/
hr.16-21 Several studies have indicated
a median effective dose of 0.6–1 mg/
kg/hr.16,17,20,21 Carroll et al.18 reported
a median effective dose of 0.7 mg/kg/
hr in patients who received dexme-
detomidine for more than 24 hours
(either as an adjunct, in anticipation
of extubation, or alone for sedation)
and a median effective dose of 0.9
m g/kg/hr when dexmedetomidine
was used as an adjunct for sedation.
Patients who received dexmedetomi-
dine for more than 24 hours required
higher median doses (0.5 mg/kg/hr
versus 1 mg/kg/hr), indicating that
there may be some tachyphylaxis
with extended use. The variability in
the dosage range of dexmedetomi-
dine observed in the study may be a
clinical Consultation
reflection of the small sample size of
patients and substantial variability of
individual patient response, empha-
sizing the need for clinical trials to
determine effective dosing.
Literature review. A PubMed
search using the terms pediatric
narcotic withdrawal, dexmedeto-
midine, Precedex, clonidine, and
pediatric sedation was performed
to identify articles addressing use
of dexmedetomidine hydrochloride
for narcotic withdrawal in pediatric
patients. The published literature
on dexmedetomidine use for opioid
withdrawal mainly consists of sev-
eral case studies and two retrospec-
tive reviews involving a total of 20
pediatric patients.16,22-25
Bejian and colleagues17 found a
decrease in total daily doses of fen-
tanyl (mean ± S.D., 16.58 ± 4.2 mg/kg/
day versus 47.5 ± 15.1 mg/kg/day) and
midazolam (0.26 ± 0.1 mg/kg/day
versus 1.08 ± 0.47 mg/kg/day) in 45
pediatric patients who received dex-
medetomidine when compared with
those who did not receive the drug.
The decreased opioid requirements
reported with dexmedetomidine use
might help reduce the rate of with-
drawal and allow shorter tapering
schedules.
Finkel et al.16 discussed two pe-
diatric patients who received dex-
medetomidine for prevention of
withdrawal and to aid in acute
discontinuation of fentanyl and mid-
azolam continuous infusions after
cardiac transplantation. Bolus doses
of dexmedetomidine were used (1
mg/kg over 10 minutes), followed by
a continuous infusion of 0.8–1 mg/
kg/hr for the first 10 postoperative
days. In one case, bolus doses of
dexmedetomidine were given when
signs of withdrawal were seen; dex-
medetomidine was tapered on days
11 and 16 and then discontinued.
A similar protocol was followed for
the second patient. In both cases, the
patients responded to dexmedeto-
midine boluses for control of with-
drawal symptoms, which allowed for
Am J Health-Syst Pharm—Vol 68 Jul 1, 2011
Dexmedetomidine
continued tapering of fentanyl and
midazolam continuous infusions.16
Finkel and Elrefai25 reported the
case of an eight-month-old infant
who had been mechanically venti-
lated since birth in the neonatal in-
tensive care unit. At the age of seven
months, the patient underwent a tra-
cheostomy; 253 mg/kg/day of fentan-
yl and 20.3 mg/kg/day of midazolam
were required for adequate sedation.
Dexmedetomidine was used for
prevention of narcotic withdrawal.
A Bispectral Index Score (BIS, a unit-
less scale of 0–100 on which 0 indi-
cates coma, 60–90 indicates sedation,
and 100 indicates awake) was used
to titrate dexmedetomidine with a
target BIS of 60–80. Dexmedetomi-
dine was initiated immediately after
discontinuation of the fentanyl and
midazolam continuous infusions
at a bolus dose of 1 mg/kg over 10
minutes and a continuous infusion
rate of 0.2–0.7 mg/kg/hr. Bolus doses
were given every six hours until the
cumulative dose was 0.7 mg/kg/hr
and the BIS was over 80, or until arte-
rial blood pressures were greater than
20% of baseline. Bolus doses were
needed on days 2–4. Dexmedetomi-
dine was tapered on day 7, and no
symptoms of narcotic withdrawal
were seen in the following two weeks.
Baddigam et al. 22 reported on
three pediatric patient cases in which
dexmedetomidine was used for
treatment of withdrawal syndromes.
In one case, dexmedetomidine was
started due to a diagnosis of drug
and substance withdrawal. In the
other two cases, dexmedetomidine
was used when withdrawal symp-
toms were observed three to five
days after surgery while the patients
were receiving continuous infusion
fentanyl (4–6 mg/kg/hr) and inter-
mittent midazolam (0.1 mg/kg/dose
every two hours as needed); one of
those patients required four mid-
azolam doses per day, and the other
required four to eight doses per day.
Dexmedetomidine was started after
withdrawal symptoms were seen us-
1235
 clinical consultation
ing a bolus dose of 0.5 mg/kg over
15 minutes, followed by a continu-
ous infusion at 0.25 mg/kg/hr, with
a maximum infusion rate of 0.6 mg/
kg/hr. All three patients experienced
amelioration of their withdrawal
symptoms (hypertension, tachycar-
dia, diaphoresis, agitation, and trem-
ors) with dexmedetomidine.
Two retrospective studies assessed
the use of dexmedetomidine for
opioid withdrawal in pediatric pa-
tients.23,24 The first study reported on
seven infants (3–24 months old) who
had received continuous fentanyl
infusions with intermittent mid-
azolam for extubation procedures.24
Fentanyl and midazolam exposure
was four to nine days, with a fentanyl
infusion range of 4–9 mg/kg/hr. All
seven patients had Finnegan scores
of 12 or more along with signs and
symptoms of severe withdrawal.
Dexmedetomidine was given for
treatment of withdrawal as a bolus of
0.5 mg/kg over 10 minutes, followed
by a continuous infusion at 0.5 mg/
kg/hr. After the addition of dexme-
detomidine, Finnegan scores were
consistently 7 or lower. The dexme-
detomidine dose was decreased by
0.1 mg/kg/hr every 12–24 hours.24
The second study assessed use of a
subcutaneous continuous infusion of
dexmedetomidine for prevention or
treatment of withdrawal in seven pe-
diatric patients (the patients required
i.v. access solely for the purpose
of the dexmedetomidine continu-
ous infusion).23 The subcutaneous
continuous infusion was initiated
at the same rate as the i.v. infusion
(0.8–1.4 mg/kg/hr). Subcutaneous
dexmedetomidine was used for pe-
riods of four to seven days, with no
reported adverse effects and modi-
fied Finnegan scores ranging from
3 to 7, suggesting that subcutaneous
continuous infusion may be an al-
ternative to i.v. continuous infusion
for delivery of dexmedetomidine.23
Limitations of published evi-
dence. The available literature on
dexmedetomidine use for prevention
1236 Am J Health-Syst Pharm—Vol 68 Jul 1, 2011
Dexmedetomidine
or treatment of narcotic withdrawal
is limited. While the studies and case
reports described here provide useful
insights, they involved a total of only
20 patients, and 90% of the patients
were less than four years old. In ad-
dition, all five case reports (most by
the same author) described the use
of bolus doses; although it is not
reported in the literature, many in-
stitutions do not use bolus doses of
dexmedetomidine due to the risk of
adverse events. Moreover, the range
of reported continuous infusion
rates is wide, and rates were typi-
cally titrated to patient response,
with the dose-limiting factors being
hypotension and bradycardia. In ad-
dition to those issues, the package
insert states that dexmedetomidine
is to be used for less than 24 hr,26
but in all of the reports described
here, dexmedetomidine was used
for 2–16 days without additional
adverse events or development of
withdrawal symptoms.
Adverse events. Dexmedetomi-
dine is an imidazole compound
specific for the a2-adrenergic re-
ceptors in the brain and spinal
cord. Its inhibition of neuronal fir-
ing in the CNS also results in hypo-
tension and bradycardia, which are
dose-dependent, common adverse
effects of dexmedetomidine.22 Dex-
medetomidine does not have direct
effects on the hemodynamics of the
heart. Bolus doses of dexmedeto-
midine have been found to be com-
monly associated with hypotension
and bradycardia, which are thought
to be mediated by the effects of
dexmedetomidine on a1-adrenergic
receptors in the brain and spinal cord
at high doses. In addition, it has been
hypothesized that rapid boluses may
produce some peripheral a2B-receptor
stimulation; that is overcome with
slow infusion.
Few studies have been conducted
to assess adverse events associ-
ated with use of dexmedetomidine
in pediatric patients. In adults, the
most common adverse events are
hypotension (30% of reported cases),
hypertension (12% of cases), and
bradycardia (9% of cases).27 Honey et
al.28 conducted a retrospective study
of 36 pediatric patients (median age,
3.2 years; range, 0.01–16.75 years)
who received dexmedetomidine for
at least two hours during a total of 41
infusions. They found an overall ad-
verse event rate of 51%; bradycardia
and hypotension occurred in 15%
and 22% of cases, respectively. The
frequency of hypotension and bra-
dycardia reported by Honey et al.28
is higher than that reported in other
retrospective studies.19 In the review
conducted by Carroll et al.,18 brady-
cardia was seen in 3% of cases and
hypotension in 9% of cases, which is
consistent with the findings of other
studies. The patients in the study by
Carroll et al. ranged from 0.1 to 17.2
years of age, with a median age of 1.5
years. Hypotension and bradycardia
are thought to be associated more
with use of bolus doses than with
continuous infusion of dexmedeto-
midine; that might explain the dis-
crepant adverse-event rates reported
in the study by Carroll et al.,18 which
did not include patients who received
bolus doses of dexmedetomidine,
and the study by Honey et al.,28 in
which 43.9% of patients received
bolus doses.
There is a potential for withdrawal
after the discontinuation of long-
term infusions of dexmedetomidine.
Defining long-term dexmedetomi-
dine use is difficult. As previously
mentioned, dexmedetomidine has a
mechanism of action similar to that
of clonidine, and withdrawal symp-
toms have been reported after rapid
discontinuation of long-term cloni-
dine therapy administered by oral,
epidural, and transdermal routes.29
While more data on withdrawal after
rapid discontinuation of dexmedeto-
midine are needed, a few case reports
indicate that tolerance and with-
drawal phenomena can occur.7,30,31
Proposed mechanisms for develop-
ment of tolerance include receptor

desensitization via loss of receptors
or receptor–effector uncoupling.
Relief of withdrawal symptoms
such as hypertension, tachycardia,
emesis, agitation, facial drooping,
decreased verbal communication,
and tonic–clonic seizures has been
reported with reinitiation of dexme-
detomidine.30 Unlike the reported
experience with other continuous
infusion medications for seda-
tion and analgesia, the symptoms
of dexmedetomidine withdrawal
(e.g., agitation, irritability, dystonic
movements, centrally mediated re-
bound hypertension) appear to be
CNS related, with no hemodynamic
manifestations.30,31
Discussion
Dexmedetomidine is an a 2 -
agonist whose use in the PICU has
increased in the last few years as an
adjunct to sedation and analgesia.
The use and typical dosages of dex-
medetomidine vary, primarily due to
concern about potential hypotension
and bradycardia, which have been
reported in the published literature
in association with the use of bolus
doses. When bolus doses are used, a
typical loading dose is 0.5–1 mg/kg
given intravenously over 10 minutes;
bolus doses are followed by a con-
tinuous infusion of 0.1–1.4 mg/kg/hr.
Dexmedetomidine has the ben-
efits of being an effective adjunct
therapy for sedation and analgesia
without producing the respira-
tory depression seen with most other
sedatives and analgesics. In addition,
when used as an adjunct, dexme-
detomidine allows for decreased
fentanyl and midazo­lam require-
ments. Common adverse effects of
dexmedetomidine use are hypoten-
sion and bradycardia; these effects
are thought to be related to the use of
bolus doses, high cumulative doses,
and longer duration of therapy. The
majority of published reports about
the use of dexmedetomidine in pedi-
atric patients only describe its use for
analgesia and sedation.
clinical Consultation
Dexmedetomidine has a mecha-
nism of action similar to that of
clonidine, with the benefit of greater
selectivity for the a2-receptor. Dex-
medetomidine may have a role in
decreasing the occurrence of narcotic
withdrawal after discontinuation
of continuous infusion opioids and
benzodiazepines in pediatric pa-
tients. While the available evidence
demonstrates the usefulness of dex-
medetomidine in pediatric critical
care, questions persist as to the drug’s
safety and efficacy for analgesia and
sedation. Data on use of dexmedeto-
midine specifically for the prevention
and treatment of opioid and ben-
zodiazepine withdrawal are limited,
indicating the need for additional
well-designed studies exploring its
use for pediatric narcotic withdrawal.
Conclusion
A limited body of published evi-
dence from retrospective studies and
case reports suggests a potential role
for dexmedetomidine as an adjunct
therapy to provide sedation and an-
algesia to reduce narcotic withdrawal
symptoms in pediatric patients.
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